THE HISTORY OF DRUGS

I wonder what's around the bend? said the explorer

I wonder what that plant is? said the collector

I wonder what's in it? said the chemist

I wonder what activity it has? said the pharmacologist

I wonder if it'll work in this case? said the physician

I hope she lives! said the father

Please God! said the mother

I think she'll be all right in the morning, said the nurse

– MARGARET KREIG Green Medicine

Ever since human beings first walked this earth they have searched for materials that would ease their suffering. As time went on they came to know which plants would feed their hunger, which would poison, and which would heal. In the ancient Sumerian town of Nippur, prescriptions were written on clay tablets and from these we know that over 4,000 years ago people used flowers, seeds, leaves, fruits, roots, and barks in their medicines. Among the plants they used were thyme, myrrh, and pine — which are still used today in the form of essential oils — and willow, the source of aspirin.

Aspirin is another name for acetyl-salicylic acid, a synthetic first produced in 1899 and derived from salicin, the active ingredient, named after salix — a family of willow tree. For thousands of years resins and juices from the bark and leaves of the willow have been used to treat rheumatism, neuralgia, and other ailments. The scientific history of the willow is traced to an 18th century clergyman, Edmund Stone, who had by recommendation or accident acquired the habit of chewing the bark. Interestingly, salicin is also a drug for the tree itself — conferring "systematic acquired resistance" on it, according to scientists at the Agricultural Biotechnology Research Unit of Ciba-Geigy, the multinational chemical company. Apparently, the willow trees use it to ward off infections, which they are prone to because they often grow by stagnant water.

Malaria has killed more people in this world than any other disease. The first drug treatment was quinine, which continues to be used against strains of the disease that are resistant to newer antimalarials, and is more commonly prescribed to prevent painful leg cramps at night. The source of this drug is the bark of a flowering evergreen, Cinchona, which grows on the Andean slopes of South America. The bark, first imported to Europe in 1645, was widely used as an antimalarial although its mysteries were not uncovered until 1819 when pharmaceutical chemists extracted one of the alkaloids and named it quinine after the Peruvian Indian word quina-quina, the "bark of barks."

As people explored their natural environment, they inevitably came across those plants that have an effect on the mind. So it was in India and Africa where for hundreds and perhaps thousands of years people used the root of related species of rauwolfia as a tranquilizer and treatment for "moon madness" — lunacy. In 1925 an eminent Nigerian living in London became psychotic but the doctors treating him couldn't help. The witchdoctor was summoned and arrived with his rauwolfia root — which did the trick. The active substances in rauwolfia (named after Leonhard Rauwolf, the 16th century physician and plant explorer) were isolated in the late 1940s by Indian scientists and after more work by the Swiss drug company, Ciba-Geigy, the first mind or mood altering drug based on rauwolfia alkaloids, reserpine, hit the market. And what a market it was — $80 million by the mid 1970s.

Not all alkaloids are so easy to reproduce chemically because they have large compounds which are difficult to synthesize. An example of this is the Madagas-can Periwinkle, the source of vincristine sulfate, an essential drug in any pharmacy dealing with childhood leukemia and certain lymphomas. It still takes 12 tons of crushed leaves to produce one ounce of the drug — also the source of Vinblastine, used to treat Hodgkin's disease. Over the years untold suffering has been alleviated by this innocent-looking pink and white ornamental, Catharanthus roseus, which gardeners appropriately call "bright eyes." Cancer treatment would be a harder task today without the 70% of antitumor drugs derived from native medicines.

Originally, all drugs were natural. The Ayurvedic system of medicine, thought to be at least 5,000 years old, is still extensively used in the Indian subcontinent and is studied by many Western medics as well. The text books mention 8,000 different natural medicines, using plant, animal, and mineral materials. Chinese herbal medicine is also becoming popular in the West, and of course continues to be of central importance in the materia medica of China. The first drug directory that we know of is the 2800 B.C. Pen Ts'ao, written by herbalist Shen Nung. In the Western tradition, credit for establishing medical botany as an applied science is given to the Greek physician Pedanios Dioscorides who in 78 A.D. published his Materia Medica, which detailed the properties of about 600 medicinal plants, as well as the medicinal value of certain animal products. Books such as these, recording the properties of natural products, were the mainstay of western medicine for about 1,400 years. The concept of medicinal chemistry was introduced in the 1520s by Paracelsus, a Swiss pharmacist-physician whose "real" name was Theophrastus Bombastus von Hohenheim. Paracelsus advocated the use of mineral salts and acids and experimented with various chemical processes including distillation. It would be another three hundred years before medical chemistry really took off, however, inspired by the German apothecary's assistant Friedrich Serturner, who in 1806 isolated the first active alkaloid of a natural drug — raw opium from the poppy Papaver somniferum. Serturner named it morphine after Morpheus, the Greek god of Dreams. Codeine is a derivative of morphine.

The history of drugs clearly shows the source of inspiration — nature. However, nature has its disadvantages. Imagine yourself the manager of a drug company looking at your storehouse full of bags of herbs, barks, roots, leaves, and flowers imported from all over the world. You start thinking about what could go wrong with your supplies. Natural products are vulnerable to adverse weather conditions, including flood and drought, as well as to pest catastrophes. But if just one of these raw materials fails to make it to the factory, drugs cannot be made and people die. Also, natural raw materials are unpredictable in terms of the quantity of active ingredients they contain, and huge quantities of the stuff have to be processed to produce small quantities of the required drug. On top of that, the raw material has to be purified and quantified — all of which is more effort. You can see why chemists tried to find a way of creating the active ingredients of medicinal plants by more easily controlled, chemical means.

Over the years we have seen a major shift of emphasis. To begin with, natural products were either the raw material of drugs, or the inspiration for chemical copies. As chemists became more confident, they made cocktails using more and more compounds — some natural, some not. Nowadays, scientists create chemical cocktails that have little to do with nature as we know it. What effect these will have on the population is still little understood because long-term studies cannot yet be made. Unlike natural drugs, these chemical cocktails have new molecular arrangements that haven't been on trial for thousands of years. Indeed, their trials are of necessity rather short because a company has to register the 30-year patent for the new drug before it can carry out trials. That patent is liable to run out if the company doesn't get its act together quickly and produce the evidence of efficacy and safety required to get a product license. The quicker a trial can be done, the more time there is left on the patent in which the company can exclusively exploit their invention.

Chemical companies are still interested in nature. In the deepest jungles and the most far-off corners of the earth, representatives from drug companies continue to scour the landscape looking for new varieties of nature to exploit. They are not intending, however, to manage huge fields of these natural products, and extract from them the drug required. They are simply going to try to isolate the active substances and replicate them in the laboratory. In their dreams, scientists imagine a future biotechnology when the physiological and psychoactive substances in plants can be produced cheaply and easily using microbes or whatever.

Biotechnology is here, however. Take Hirudin, for example, the latest potential drug from Ciba-Geigy, which is at the human trials stage. The leech Hirudo medicinalis was used for centuries to draw blood from patients. The saliva of the leech is now known to contain substances which act as a powerful and highly predictable anticoagulant, which may be very useful in the prevention of thrombosis, stroke and heart attack — the western world's largest killer disease. The problem is, it takes the saliva from 10,000 leeches to make a single human treatment and, I imagine, extracting it is quite a job! Biotechnology, however, gets around the problem by taking the appropriate gene from the leech and putting it in yeast cells, which produce Hirudin molecules.

New discoveries continue to be made. In a recent article in the Lancet, co-authored by Nobel Laureate B.S. Blumberg, clinical research was presented which proved that the hepatitis B virus was eliminated from the bodies of 59% of people treated for thirty days with dried and powdered Phyllanthus amarus, a plant used for over 2,000 years in Ayurvedic medicine to treat liver disease, including jaundice. The plant has also been used in China, the Philippines, Cuba, Nigeria, Guam, East and West Africa, the Caribbean, and Central and South America. Despite the fact that the plant is used so extensively, and the fact that it has now been studied for over ten years, and has shown no toxic or side effects in animals or humans, it will probably never reach the marketplace in Britain or America. Phyllanthus needs more than the keen advocacy of the eminent Blumberg, who got his Nobel prize for discovering the hepatitis B virus and developing the blood test to detect it. Phyllanthus needs tens of millions of dollars to go through clinical testing, and chemical companies aren't going to support that work because, to date, they have no intention of selling herbs. They may well look at Phyllanthus, and try to copy its active constituents, but that is another matter.

In the land of the BMW, Germany, things are different. The laws allow natural medicines to be sold, but as food supplements without any indication of use on the label. Even so, everyone knows what they are for. For example, we see ginkgo biloba extract, taken from the plant much used in herbalism, becoming a best-selling prescription drug in Germany — where it is used to stimulate cerebral circulation in the elderly.

I don't understand why chemical companies don't switch their attention to producing extracts or essential oils from natural plants. It may have something to do with the difficulty in patenting remedies that have been known for centuries. But it is possible to quite easily extract the active constituents of plants, and it's much easier than trying to replicate their extraordinarily complex powers in chemistry. Lavender is the classic case in point. It is the treatment par excellence for burns. Put on badly burnt skin, lavender nothing short of miraculously returns the burnt skin to normal, and very, very quickly. But, for all the work on it, lavender will not easily give up her secrets. Chemists can make a liquid that smells like lavender, and they can even break it apart and label a certain number of its constituents, but they cannot make a substance that is like lavender that heals burns. As systems of analysis get better, more molecular and other secrets will be revealed. Meanwhile, in burn departments in hospitals, people suffer.

Of course science has made great strides in the field of medicine, and we all have reason to be grateful, but let us not forget the relationship between science and nature. Science looks to nature in amazement, tries to break it apart and copy it. Nature makes cells and gets them to interact in unbelievably complex ways, while the whole of science and technology cannot between them make a single cell — plant, animal, or human. Looking at nature and science, we must ask ourselves which is the most clever?

The Shamans

Consciousness is at the core of humanity. Deprived of sight, hearing, touch, taste, and smell, we still have consciousness. It is, if you like, the essence of being, but throughout time people have strived to enlarge their consciousness or to change it so that other dimensions of being are reached. Substances which alter perception are used to put people in touch with the spirits of dead ancestors; or to seek union with the god-head; or by traditional healers who want to gain a more profound insight into the nature of a patient's disease — often perceived as the result of outside, nonmaterial, forces.

The Matse are a small, seminomadic tribe of hunter-gatherers who live in the rainforest on the Peru/Brazil border. Their pharmacopoeia includes a drug, nu-nu, which hunters use to induce visions of the future movements of animals. They see the animal situated in a particular place, and from clues in the vision, they estimate the time of day. Armed with this information, they lie in wait and make the kill. Peter Gorman may be the only westerner who has tried nu-nu, which is blown into the nostrils down a hollow reed tube, and this is his description of the experience:

"When the nu-nu hit, it seemed to explode inside my face. It burnt my nose and I began to choke up wretched green phlegm. But the pain quickly subsided and I closed my eyes. Out of the blackness I began to have visions of animals — tapir, monkey, and wild boar — that I saw more clearly than my limited experience with them should have allowed. Then suddenly the boars stampeded in front of me."2

Gorman told the Matses what he had seen, and from the clues in his vision, the time and place of the stampede was determined. The next morning Gorman and several Indians set off for the place seen in the vision. He writes: "As we neared it, I was astounded to hear the thunderous roar of dozens of boars charging across the river in front of us. We jumped out of the boat and chased them." They returned to the village with seven boars — "enough meat for the entire village for four days."

Gorman also took another Matse drug, sapo, which is made from the secretions of a frog, dow-kiet! or phyllomedusa bicolor. The immediate physical effects of ingesting this drug were horrendous, according to Gorman's account, but the results were worth it. His hearing was greatly improved, and more besides:

"My vision, my sense of smell, everything about me felt larger than life, and my body felt immensely strong ... During the next few days, my feeling of strength didn't diminish; I could go whole days without being hungry or thirsty and move through the jungle for hours without tiring. Every sense I possessed was heightened and in tune with the environment, as though the sapo put the rhythm of the jungle into my blood."

The Matses use huge quantities of the drug sapo to do nothing less than project their animas, their spirit, into the form of an animal, which they use as a lure for real animals. Gorman's informant, Pablo, set a trap in the forest then returned to the village where he took the sapo for two days. The next morning he woke Gorman up before dawn and, with the rest of the village, rushed to the place where the trap had been set. Just as the people arrived, a tapir was approaching the trap — and was duly caught. On analysis, it turns out that sapo contains seven bioactive peptides, triggers which cause chemical reactions in the body. However, why sapo should give a person the ability to project their animas remains a mystery!